The present invention relates, by way of new industrial products, to fluorophenacyl-amine derivatives, and also to the application thereof in therapeutics as unexpectedly and significantly superior anti-anorexia nervosa agents and anti-aggressive agents as well as beta-stimulating agents and antidepressant agents
In the following specification, fluorophenacylamine derivatives are understood to mean not only compounds having a fluorophenacyl group or formula F--C.sub.6 H.sub.4 --CO--CH.sub.2 --, but also a .beta.-hydroxyfluorophenethyl group of formula F--C.sub.6 H.sub.4 --CHOH--CH.sub.2 --, which derives from the preceding one by reduction of the carbonyl function into alcohol function.
Compounds of the 2-amino-1-(halogenophenyl)-1-ethanol type are included in the formula of French patent No. 1 503 517 and presented as antidiuretic agents. However, it should be noted that this French patent describes no 1-(fluorophenyl), 1-(chlorophenyl), 1-(bromophenyl) and 1-(iodophenyl) derivatives, nor does it suggest their potential actions on the CNS.
It is known that fluorophenacyl-amine derivatives belonging to the family of 2-amino-1-(fluorophenyl)-1-ethanols have already been described. In particular, the article by A.M. Lands, J. Pharmacol. Exptl. Therap. 106, 440-443 (1952) discloses 1-(3-fluorophenyl)-2-isopropylamino-1-ethanol and 1-(3-fluorophenyl)-2-tertiary-butylamino-1-ethanol as being weak pressor agents. The article by L. Villa, et al., Il Farmaco Ed. Scientifica, 24 (No. 3), 329-340 (1969), discloses 1-(4-fluoropyhenyl)-2-isopropylamino-1-ethanol and 1-(2-fluorophenyl)-2-isopropylamino-1-ethanol. These known fluorinated products act on the CNS but they have no, or only slight, aggression-reducing effect. Further, analogous compounds are also disclosed as being adrenergic blocking agents in the article by B. Levy, et al., J. Pharamacol. Exptl. Therap., 133, 202-210 (1961); as appetite-supressing agents in U.S. Pat. Nos. 3,313,687 (Siemer) and 3,465,039 (Seimer); as CNS-stimulant and antidepressant agents in U.S. Pat. No. 3,819,706 (Mehtay) and as anti-diuretic agents in British Patent No. 1,043,510.
It has been unexpectedly found that the new fluorophenacyl-amine derivatives of the present invention, which act on the CNS, have particularly advantageous antiaggressive and anti-anorexia nervosa properties from the therapeutical standpoint.
According to the invention, a compound belonging to the family of fluorophenacyl-amine derivatives of formula: ##STR1## wherein A is CO or CHOH, and R is CH(CH.sub.3).sub.2 or C(CH.sub.3).sub.3, is recommended as new industrial product, particularly useful in therapeutics, said compound being characterized in that it is selected from the group consisting of N-(4-fluorophenacyl)-isopropylamine, N-(2-fluorophenacyl)-tertiary-butylamino, 1-(2-fluorophenyl)-2-tertiary-butylamino-1-ethanol, 1-(4-fluorophenyl)-2-tertiary-butylamino-1-ethanol, and their addition salts.
From these products, the preferred compounds from the therapeutical standpoint are N-(4-flurophenacyl)isopropylamine and its salts, particularly the hydrochloride.
Addition salts are understood here to mean the acid addition salts obtained by reacting a free base of formula I with an inorganic or organic acid, and the ammonium salts. Among the acids which may be used for salifying the bases of formula I, the following may be particularly mentioned: hydrochloric, hydrobromic, nitric, sulphuric, acetic, propionic, oxalic, fumaric, maleic, succinic, benzoic, cinnamic, mandelic, citric, malic, lactic, tartaric, p-toluenesulphonic and methanesulphonic acids. Among the compounds enabling ammonium salts to be obtained, particular mention may be made of ICH.sub.3 and CICH.sub.3. The acid addition salts are the preferred salts, and, among the latter, the most advantageous are the hydrochlorides.
The fluorophenacyl-amine derivatives of this invention may be prepared according to a method known per se, by application of conventional reactional mechanisms. The recommended process for preparation consists of the following:
(1) in obtaining a "carbonyl" compound (A =CO) by reacting a fluorophenacyl halide of formula ##STR2## (wherein X.sub.1 is Cl or Br) with an amine of formula EQU H.sub.2 NR (III)
(wherein R is defined as hereinabove), under reflux for at least 1 hour in an alcohol, preferably methanol, then
(2) if necessary, in obtaining an "alcohol" compound (A=CHOH) by reducing the corresponding carbonyl derivative, in particular with NaBH.sub.4.
The compounds according to the invention are all active on the CNS and also have interesting cardiovascular effects. In particular, they act on the CNS as sedative agents, antidepressants and superior antiaggressive agents and are unexpectedly indicated in the treatment of anorexia nervosa as well as depression.